The study of innate immunity has undergone a renaissance, fueled by molecular identification of critical pattern recognition receptors and signaling pathways involved in pathogen recognition by the innate immune system. Innate immune responses are tightly regulated. Responses that are delayed or of insufficient vigor can lead to a failure to control infection. On the other hand, too vigorous a response to an infecting pathogen can itself be harmful - something seen in the hyperactivation of innate immune responses that marks microbial sepsis and septic shock. Dysregulation of innate immunity is thought to be central to the pathogenesis of the diseases caused by many microbial pathogens that are of current concern as Category A and B biological threat agents. Conversely, well regulated innate immune responses are thought to be key to successful immune responses to these pathogens, as well as to successful vaccination against these and other infectious agents. Toll-like receptors (TLR) are signaling receptors that are central to innate immune recognition of a variety of pathogens. As might be expected, signaling through TLRs is tightly regulated at a variety of levels. We have recently discovered a novel mechanism of TLR regulation: the "B cell-specific" TLR homologue, RP105. Notably: (a) RP105 is not B cell-specific; RP105 expression mirrors that of TLR4 expression in antigen presenting cells (monocytes, macrophages, dendritic cells); (b) RP 105 acts as a specific inhibitor of TLR4 signaling in cell lines; (c) dendritic cells and macrophages from RP105-/- mice produce increased amounts of proinflammatory and immunoregulatory cytokines in response to TLR4-specific ligands, compared with wild-type controls; and (d) TLR4-driven cytokine production is similarly elevated in vivo in RP105-/- mice. The central hypothesis underlying these studies is thus that RP105 is a physiological regulator of TLR4 signaling and TLR4-driven immune responses. The long-term goal of this work is definition of the molecular mechanisms that underlie the generation and regulation of successful immune responses to biological threat agents and other pathogens. The studies in this proposal aim at mechanistic definition, both in vitro and in vivo, of the role of RP105 in modulating TLR4 signaling and TLR4-driven immune responses.